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Journal articles on the topic 'Tissue Treg'
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1
Li, Chaoran, Andrés R. Muñoz-Rojas, Gang Wang, Alexander O. Mann, Christophe Benoist, and Diane Mathis. "PPARγ marks splenic precursors of multiple nonlymphoid-tissue Treg compartments." Proceedings of the National Academy of Sciences 118, no. 13 (March 22, 2021): e2025197118. http://dx.doi.org/10.1073/pnas.2025197118.
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Foxp3+CD4+ regulatory T cells (Tregs) regulate most types of immune response as well as several processes important for tissue homeostasis, for example, metabolism and repair. Dedicated Treg compartments—with distinct transcriptomes, T cell receptor repertoires, and growth/survival factor dependencies—have been identified in several nonlymphoid tissues. These Tregs are specifically adapted to function and operate in their home tissue—When, where, and how do they take on their specialized characteristics? We recently reported that a splenic Treg population expressing low levels of the transcription factor PPARγ (peroxisome proliferator-activated receptor gamma) contains precursors of Tregs residing in visceral adipose tissue. This finding made sense given that PPARγ, the “master regulator” of adipocyte differentiation, is required for the accumulation and function of Tregs in visceral adipose tissue but not in lymphoid tissues. Here we use single-cell RNA sequencing, single-cell Tcra and Tcrb sequencing, and adoptive-transfer experiments to show that, unexpectedly, the splenic PPARγlo Treg population is transcriptionally heterogeneous and engenders Tregs in multiple nonlymphoid tissues beyond visceral adipose tissue, such as skin and liver. The existence of a general pool of splenic precursors for nonlymphoid-tissue Tregs opens possibilities for regulating their emergence experimentally or therapeutically.
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Mailloux, Adam William, Deanne M. R. Lathers, and M. Rita I. Young. "Lewis Lung Carcinoma-derived CCL22 recruitment of T regulatory cells (B148)." Journal of Immunology 178, no. 1_Supplement (April 1, 2007): LB31. http://dx.doi.org/10.4049/jimmunol.178.supp.b148.
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Abstract Two aspects of cancer progression that contribute to malignancy are the ability of the tumor to metastasize to remote locations in the body, and the ability to evade effective host anti-tumor immune responses. It has been shown that T regulatory cells (Treg) can inhibit immune effector cell function and aid in anti-tumor immune evasion. Several types of tumors have elevated Treg numbers, and it is believed that tumors may actively recruit these cell types. Treg migration is induced by several chemokines and their receptors such as CCL22 and CCR4. Here, we use flow cytometry to analyze CCR4 expression on T cell populations and show that Tregs express more CCR4 than any other T-cell type. We also used ELISA to compare CCL22 secretion levels in normal and Lewis Lung Carcinoma (LLC) bearing lung tissue. While high basal levels of CCL22 are secreted from normal lung tissue, even higher levels are secreted by LLC bearing lung tissue. In addition, we used media conditioned on these tissues in transwell migration assays to measure preferential Treg chemoattraction. Normal lung tissue induced high levels of selective Treg chemoattraction, while LLC bearing lung selectively attracted even greater numbers of Tregs. These data suggest that normal lung tissue may be able to recruit elevated levels of immune inhibitory Tregs through the secretion of CCL22 prior to metastasis, and that once LLC metastasis occurs, both CCL22 and Treg levels increase even further.
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Camirand, Geoffrey, and David Rothstein. "Treg suppressor function in inflamed peripheral tissue and lymphoid tissue occurs through distinct mechanisms (IRC11P.426)." Journal of Immunology 194, no. 1_Supplement (May 1, 2015): 197.8. http://dx.doi.org/10.4049/jimmunol.194.supp.197.8.
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Abstract The mechanisms by which Treg (CD4+Foxp3+) affect DC function and modulate immunity in inflamed non-lymphoid tissues remain poorly understood. Here, we used 2-photon intravital microscopy to visualize how Treg suppressor function operates within allografts. To restrain the immune reaction to the transplant site, we adoptively transferred effector T cells (Teff), wt Treg, or both (2-3x106 each) to B6 mice lacking 2° lymphoid organs (SLO; splenectomized LTβR-/-) 3-4 days after transplantation of BALB/c islets. Teff alone induced acute allograft rejection. However, the co-transfer of Teff + wt Treg led to long-term allograft survival in ~50% of recipients. Intravital microscopy of transplanted islets on day 2 showed that wt Treg infiltrated the peri-islet region, where they predominantly made contacts with DCs. Wt Treg restrained the motility parameters of Teff in the peri-islet region, reduced Teff-DC contacts, and decreased Teff intra-islet infiltration (insulitis), compared to Teff alone. Treg constitutively express the ecto-nucleotidase CD73, which generates anti-inflammatory adenosine from AMP. CD73-/- mice do not develop autoimmunity, and CD73-/- Treg are potent suppressors in vitro. In contrast, CD73-/- Tregs were unable to prevent allograft rejection by Teff, despite their presence at the graft site. These results indicate that Treg function does not require priming in SLO and that their mechanisms of action may differ from those used in SLO.
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Zhang, Chaoqi, Lifeng Li, Kexin Feng, Daoyang Fan, Wenhua Xue, and Jingli Lu. "‘Repair’ Treg Cells in Tissue Injury." Cellular Physiology and Biochemistry 43, no. 6 (2017): 2155–69. http://dx.doi.org/10.1159/000484295.
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Studies in mice and humans have elucidated an important role for Tregs in promoting tissue repair and restoring tissue integrity. Emerging evidence has revealed that Tregs promoted wound healing and repair processes at multiple tissue sites, such as the heart, liver, kidney, muscle, lung, bone and central nervous system. The localization of repair Tregs in the lung, muscle and liver exhibited unique phenotypes and functions. Epidermal growth factor receptor, amphiregulin, CD73/CD39 and keratinocyte growth factor are important repair factors that are produced or expressed by repair Tregs; these factors coordinate with parenchymal cells to limit injury and promote repair. In addition, repair Tregs can be modulated by IL-33/ST2, TCR signals and other cytokines in the context of injured microenvironment cues. In this review, we provide an overview of the emerging knowledge about Treg-mediated repair in damaged tissues and organs.
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Fu, Wenxian. "A tissue-resident macrophage specific coinhibitory molecule promotes regulatory T cell differentiation and stability." Journal of Immunology 196, no. 1_Supplement (May 1, 2016): 125.5. http://dx.doi.org/10.4049/jimmunol.196.supp.125.5.
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Abstract CD4+ Foxp3+ regulatory T (Treg) cells are key players in immune tolerance and tissue homeostasis. Their impact on tissue homeostasis has been further reinforced by recent studies showing that Tregs in tissue control non-immunological processes. However, how Treg cell differentiation and function are influenced by tissue-derived signals remain poorly understood. We here show that a specific subset of tissue-resident macrophages can promote the differentiation and stability of Tregs. This subset of tissue-resident macrophages distinctively express complement receptor of the immunoglobulin superfamily (CRIg). The phenotype of these macrophages are F4/80hi CRIg+. Our previous studies have found that CRIg acts a coinhibitory molecule to suppress T cell proliferation. We find that in addition to dampening effector T cell proliferation, CRIg promotes the conversion of induced Treg cells (iTreg), by synergizing with TGFβ. CRIg also stabilizes Foxp3 expression in induced Tregs. In vivo CRIg-Ig fusion protein treatment increases Treg proportion, particularly in tissue (islets) of NOD mice, a commonly used animal model for autoimmune diabetes. Together, these data reveal a novel mechanism of shaping Treg pool and function by tissue-resident macrophages. CRIg may represent a novel means to generate ‘stable’ iTregs, which remains unmet need in Treg-based therapy.
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Oleinik, E. K., A. V. Churov, and V. M. Oleinik. "IMMUNOLOGICAL MEMORY: THE ROLE OF REGULATORY CELLS (TREGS)." Medical Immunology (Russia) 20, no. 5 (November 6, 2018): 613–20. http://dx.doi.org/10.15789/1563-0625-2018-5-613-620.
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Memory T cells are necessary for development of the immune response and represent one of the most numerous population of human T lymphocytes. On the contrary, suppressive regulatory T cells (Tregs) may terminate the immune response and help to maintain tolerance to self-antigens. These important groups of cells are consisting of different subpopulations and retaining throughout life. However, today there is yet no clear understanding of how the relations between these two groups of cells are formed. In this work we consider possible ways of development and maintenance of CD4+ T cell memory and role of Tregs in these processes. Mechanisms of a differentiation of memory T cells, Tregs and recently described memory Tregs are discussed. The functional and genetic characteristics of these cells are compared. Division of cells according to the functional profile allows drawing parallels between memory T cells and Tregs. These two groups are consisted of central circulating populations (Tc), effector which can migrate toward specific tissues (Te) and tissue-resident cells (Tr), which are staying in peripheral tissues. The similar structural organization of Tregs and memory T cells, existence of transitional forms of tissue-resident Treg subpopulations with properties of memory cells assumes existence of close interrelation between these groups of lymphocytes. The conversion of CD4+ memory T cells into FoxP3-expressing Tregs is one of possible mechanisms of communication between these two groups. The memory Treg-cells with T cell and memory Treg-cell properties can represent a transitional stage of differentiation. On the other side, Treg cells can differentiate independently of memory T cells and accumulate during life in the form of memory Treg cells. The supressor function of Tregs is also necessary as well as function of memory T cells to develop the immune response. It is possible, that a subset of Treg cells undergoes selection in thymus and constitutively express TCR-receptors having affinity with peripheral tissues. Further, these committed cells can be settled into tissues and become tissue-resident Treg cells which maintain regional T cell memory. Tregs can represent the “mirror image” of the structural organization of memory T cells, but with the return sign – the sign of suppression. The quantitative ratio of Tregs and memory T cells (CD4+CD45RO+CD25hiFoxP3+/CD4+CD45RO+CD25-FoxP3-), perhaps, is important criterion for functional assessment of immune system. The balance between these functionally opposite cell subsets has to provide stable functioning of immune system.
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Salama, Paul, Michael Phillips, Fabienne Grieu, Melinda Morris, Nik Zeps, David Joseph, Cameron Platell, and Barry Iacopetta. "Tumor-Infiltrating FOXP3+ T Regulatory Cells Show Strong Prognostic Significance in Colorectal Cancer." Journal of Clinical Oncology 27, no. 2 (January 10, 2009): 186–92. http://dx.doi.org/10.1200/jco.2008.18.7229.
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Purpose To determine the prognostic significance of FOXP3+ lymphocyte (Treg) density in colorectal cancer compared with conventional histopathologic features and with CD8+ and CD45RO+ lymphocyte densities. Patients and Methods Tissue microarrays and immunohistochemistry were used to assess the densities of CD8+, CD45RO+, and FOXP3+ lymphocytes in tumor tissue and normal colonic mucosa from 967 stage II and stage III colorectal cancers. These were evaluated for associations with histopathologic features and patient survival. Results FOXP3+ Treg density was higher in tumor tissue compared with normal colonic mucosa, whereas CD8+ and CD45RO+ cell densities were lower. FOXP3+ Tregs were not associated with any histopathologic features, with the exception of tumor stage. Multivariate analysis showed that stage, vascular invasion, and FOXP3+ Treg density in normal and tumor tissue were independent prognostic indicators, but not CD8+ and CD45RO+. High FOXP3+ Treg density in normal mucosa was associated with worse prognosis (hazard ratio [HR] = 1.51; 95% CI, 1.07 to 2.13; P = .019). In contrast, a high density of FOXP3+ Tregs in tumor tissue was associated with improved survival (HR = 0.54; 95% CI, 0.38 to 0.77; P = .001). Conclusion FOXP3+ Treg density in normal and tumor tissue had stronger prognostic significance in colorectal cancer compared with CD8+ and CD45RO+ lymphocytes. The finding of improved survival associated with a high density of tumor-infiltrating FOXP3+ Tregs in colorectal cancer contrasts with several other solid cancer types. The inclusion of FOXP3+ Treg density may help to improve the prognostication of early-stage colorectal cancer.
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Moreau, Joshua Michael, Devi P. Boda, and Michael D. Rosenblum. "Regulatory T cells in skin coordinate responses to epidermal injury by initiating anti-microbial immunity while delaying tissue repair." Journal of Immunology 204, no. 1_Supplement (May 1, 2020): 75.15. http://dx.doi.org/10.4049/jimmunol.204.supp.75.15.
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Abstract When barrier tissues are breached, two coordinate responses need to occur: 1) clearance of pathogens and 2) repair of damaged epithelium. Regulatory T cells (Tregs) play a major role in skin barrier repair; however, the mechanisms by which they modulate local tissue are unclear. To identify molecular pathways underpinning Treg interactions with their tissue environment, we performed single cell RNA sequencing on Tregs isolated from the skin. Our analysis revealed elevated TGFβ and integrin signaling. Specifically, we found high expression of the latent TGFβ activating integrin, αvβ8. To ascertain the physiological significance of this expression we crossed Foxp3CreERT2 and Itgb8f/fmice to generate an inducible and lineage specific system for deleting Itgb8 in Tregs. Deletion of Itgb8 led to improved epidermal healing following sterile injury. Mechanistically, Treg activation of TGFβ directly induced keratinocytes to produce the myeloid chemoattractant CXCL5, leading to neutrophilic inflammation and delayed epidermal healing. We hypothesized that during barrier injury Tregs harness integrin αvβ8 to initiate innate immune responses that temporarily override tissue reparative signals. To interrogate this hypothesis we epicutaneously infected Treg Itgb8 deleted mice with the bacterial pathogen Staphylococcus aureus. Deleted mice developed an uncontrolled infection consistent with impaired immune responses. These data indicate that activation of TGFβ by skin Tregs in response to tissue injury initiates local anti-microbial immunity. Altogether, our study uncovers a unique ability of skin Tregs to leverage TGFβ signaling to coordinate epithelial repair and innate immunity for optimized tissue healing.
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Contreras, Amanda, Darin L. Wiesner, Brock Kingstad-Bakke, Woojong Lee, John P. Svaren, Bruce S. Klein, and M. Suresh. "BACH2 in TRegs Limits the Number of Adipose Tissue Regulatory T Cells and Restrains Type 2 Immunity to Fungal Allergens." Journal of Immunology Research 2022 (August 5, 2022): 1–19. http://dx.doi.org/10.1155/2022/6789055.
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FoxP3+ regulatory T cells (Tregs) are essential for self-tolerance and moderating tissue-damaging inflammation. Tregs that develop and mature in the thymus are classified as central Tregs or effector Tregs based on whether Tregs predominately inhabit secondary lymphoid organs (central Tregs) or tissues (effector Tregs). By generating mice that are conditionally deficient for Bach2 in peripheral Tregs, we have examined the role of Bach2 in regulating Treg homeostasis and effector functions. Unlike global and T cell-specific Bach2-deficient mice, Treg-specific Bach2 ablation did not result in unprovoked TH2 inflammation in the lungs. However, Bach2 deficiency in Tregs led to augmented expressions of IRF4, BATF, and GATA3 and a significant increase in the accumulation of ST2 (IL-33R)+ve effector Tregs in the spleen and visceral adipose tissue (VAT) but not in the lungs. Enhanced Bach2-deficient Treg numbers in VAT was not linked to hyperresponsiveness to exogenous IL-33 in vivo. Most strikingly, Treg-specific Bach2 deficiency resulted in enhanced fungal protease-induced Type 2 allergic inflammation in the lungs, with no detectable effects on Type 1 responses to systemic or respiratory viral infections. In summary, we ascribe vital roles for Bach2 in peripheral Tregs: as a transcriptional checkpoint to limit precocious differentiation into effector Tregs in lymphoid tissues and as a regulator of the functional program that restrains Type 2 but not Type 1 inflammation in lungs. Results presented in this manuscript implicate dysregulated Tregs in the pathogenesis of airway hypersensitivities, asthma, and other allergic disorders.
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Fu, Wenxian, Xiaomei Yuan, Bi-Huei Yang, and Yi Dong. "A tissue-resident macrophage specific coinhibitory molecule promotes regulatory T cell differentiation and stability." Journal of Immunology 198, no. 1_Supplement (May 1, 2017): 223.14. http://dx.doi.org/10.4049/jimmunol.198.supp.223.14.
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Abstract CD4+Foxp3+ regulatory T (Treg) cells play a central role in the prevention of lethal autoimmunity and excessive inflammation. In contrast to their counterparts in lymphoid organs, Treg cells in non-lymphoid tissues acquire tissue-specific functional properties. While Treg tissue-tropisms are increasingly recognized, it remains poorly understood how tissue microenvironment influences Treg development, function and stability. Complement receptor of immunoglobulin family (CRIg) is a recently identified B7/CD28 family member. CRIg is exclusively expressed in tissue-resident macrophages. Earlier studies have found that CRIg functions as a coinhibitory molecule to suppress T cell proliferation and cytokine production. We here report a completely novel mechanism by which CRIg regulates T cell biology. We find that CRIg promotes the development of TGF-b induced regulatory T (iTreg) cells. More importantly, CRIg stabilizes the expression of Foxp3 in Treg cells by enhancing their responsiveness to IL-2. In vivo modulation of CRIg increases Treg abundancy and restores immune tolerance in autoimmune condition. In summary, these data shed new light on how tissue-resident macrophages impact tissue homeostasis by regulating the development and stability of Treg cells. CRIg may represent a tissue-specific immunomodulation to promote immune tolerance.
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Fu, Wenxian, Bi-Huei Yang, Xiaomei Yuan, and Yi Dong. "TCF/LEF family transcription factors in peripheral Treg homeostasis." Journal of Immunology 200, no. 1_Supplement (May 1, 2018): 116.11. http://dx.doi.org/10.4049/jimmunol.200.supp.116.11.
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Abstract CD4+Foxp3+ regulatory T cells (Tregs) are key players in preventing lethal autoimmunity and excessive inflammation. However, the homeostatic dynamics of Tregs in peripheral lymphoid and non-lymphoid tissues remains poorly defined. We here report that two TCF/LEF family transcription factors, LEF1 and TCF1, play critical roles in this process. Our studies led to a revised “three-stage” model of Treg peripheral differentiation, delineated by the gradient expressions of LEF1 and TCF1. We found that LEF1− TCF1− subset was bona fide effector Tregs and exhibited a core gene signature shared by various tissue Tregs. Transcriptome and conditional knockout analyses revealed that TCF1 and LEF1 may each control segregated clusters of Treg genes and regulate Treg differentiation in a “division of labor” manner. Together, these data provide novel insights into transcriptional regulation of Treg homeostasis and function.
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Smith, Alan J., Joey Liu, Ahmet Yilmaz, Valerie Wright, David Bradley, and Willa A. Hsueh. "Obesity contributes to a dysfunctional regulatory T Cell phenotype within adipose tissue." Journal of Immunology 204, no. 1_Supplement (May 1, 2020): 145.38. http://dx.doi.org/10.4049/jimmunol.204.supp.145.38.
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Abstract Adipose tissue (AT) regulatory T Cells (Tregs) play a key role in regulating inflammatory and metabolic responses. Obesity is associated with a decrease in AT Tregs as well as an increase in tissue inflammation and systemic insulin resistance in both humans and mice. We hypothesize that, in addition to the decrease in AT Treg number, there is a dysfunctional Treg phenotype caused by the increased inflammatory state within obese AT. We isolated Tregs from AT and peripheral blood(PB) from lean and obese individuals. Real-time PCR analysis was used to measure the expression of several known markers for T cell exhaustion. Protein expression of each marker was validated using FACS analysis. When compared to PB, there was a significant increase in PD-1 expression on AT Tregs. PD-1 and TIGIT were increased in Tregs isolated from obese vs. lean individuals, while CD127 expression was reduced. To determine if PD-1 expression correlates with Treg dysfunction, isolated AT and PB Tregs were added to CFSE-labeled PBMC. After 4 days culture, PB Tregs significantly inhibited proliferation but there was less suppression by AT Tregs. RNAseq analyses of PD-1 high vs. PD-1 negative AT and PB Tregs revealed a unique expression phenotype within AT Tregs. AT PD-1 high Tregs express altered metabolic and inflammatory pathways promoting loss of Tregs and increased inflammation. These data suggest that Treg exhaustion may explain the decreased Treg abundance in AT of obese individuals, which has important metabolic implications. (Partially supported by Foods for Health, a focus area of the Discovery Themes Initiative at The Ohio State University)
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Geng, JieJie, Ruo Chen, Feng-fan Yang, Peng Lin, Yu-meng Zhu, Xianghui Fu, Ke Wang, et al. "CD98-induced CD147 signaling stabilizes the Foxp3 protein to maintain tissue homeostasis." Cellular & Molecular Immunology 18, no. 12 (November 10, 2021): 2618–31. http://dx.doi.org/10.1038/s41423-021-00785-7.
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AbstractRegulatory T cell (Treg) stability is necessary for the proper control of immune activity and tissue homeostasis. However, it remains unclear whether Treg stability must be continually reinforced or is established during development under physiological conditions. Foxp3 has been characterized as a central mediator of the genetic program that governs Treg stability. Here, we demonstrate that to maintain Foxp3 protein expression, Tregs require cell-to-cell contact, which is mediated by the CD147-CD98 interaction. As Tregs are produced, CD147, which is expressed on their surface, is stimulated by CD98, which is widely expressed in the physiological environment. As a result, CD147’s intracellular domain binds to CDK2 and retains it near the membrane, leading to Foxp3 dephosphorylation and the prevention of Foxp3 degradation. In addition, the optimal distribution of Foxp3+ Tregs under both pathological and physiological conditions depends on CD98 expression. Thus, our study provides direct evidence that Foxp3-dependent Treg stability is reinforced in the periphery by the interaction between CD147 and CD98 in the surrounding environment. More importantly, Tregs with high CD147 expression effectively inhibit inflammatory responses and maintain Foxp3 stability, which has guiding significance for the application of Tregs in immunotherapy.
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Traxinger, Brianna, Sarah Vick, Valentin Voillet, Jami Erickson, Amanda Woodward-Davis, Martin Prlic, and Jennifer M. Lund. "Time- and tissue-dependent roles of regulatory T cells in the immune response to HSV-2." Journal of Immunology 206, no. 1_Supplement (May 1, 2021): 24.19. http://dx.doi.org/10.4049/jimmunol.206.supp.24.19.
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Abstract Herpes simplex virus 2 (HSV-2) is a chronic sexually transmitted infection that causes recurrent genital ulcers and increases HIV susceptibility. Efforts to design a vaccine have assumed regulatory T cells (Tregs) restrain immune activation and impede viral clearance. However, we have previously shown that in a mouse model of vaginal primary HSV-2 infection, Treg removal leads to impaired T cell priming and migration. This suggests an alternative model where Treg function is location- and context-dependent. Additionally, research suggests that tissue-resident memory T cells (Trm) localized in the vaginal tract (VT) are crucial for efficient viral control, and Trm are likely regulated by local Tregs. These findings underscore the importance of understanding the specific contributions of VT Tregs during viral infection and vaccination. We performed RNA sequencing of VT and lymph node (LN) Tregs after HSV-2 infection to reveal a highly activated transcriptional profile in VT Tregs compared to LN Tregs. Using flow cytometry, we confirmed an elevated activation and tissue residency phenotype in VT Tregs, exacerbated after HSV-2 infection. Notably, we found that VT Tregs express Granzyme B (GzmB) by both RNA-sequencing and flow cytometry. These Tregs persist in the VT up to 90 days, suggesting that they remain poised to respond to HSV-2 reencounter by restraining memory Trm to prevent tissue damage, possibly through GzmB-mediated toxicity. Tregs from healthy human VT corroborated mouse VT Treg phenotypes. These results suggest that VT Tregs are distinct and uniquely poised to respond to viral infection. Studies are ongoing to interrogate the signals that drive Treg migration into the VT and that lead to the tissue-specific Treg phenotype.
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Nguyen, Vu H., Robert Zeiser, Daniel L. daSilva, Daisy S. Chang, Andreas Beilhack, Christopher H. Contag, and Robert S. Negrin. "In vivo dynamics of regulatory T-cell trafficking and survival predict effective strategies to control graft-versus-host disease following allogeneic transplantation." Blood 109, no. 6 (November 9, 2006): 2649–56. http://dx.doi.org/10.1182/blood-2006-08-044529.
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Abstract CD4+CD25+ regulatory T cells (Tregs) suppress immune responses to alloantigens. The in vivo circulation and tissue localization of Tregs during an adaptive immune response remain unclear. We noninvasively tracked luciferase-expressing Tregs over time in an allogeneic bone marrow transplant model and demonstrated colocalization with effector T cells and initial expansion in secondary lymphoid organs before migration into inflamed tissues. Inflammation induced by irradiation and the allogeneic setting provided crucial stimuli for early Treg expansion and migration, leading to parallel reduction of effector T-cell proliferation in lymphoid organs and peripheral tissues. Treg transplants conferred long-term protection from systemic inflammatory challenge consistent with Treg in vivo survival. Suppression occurred during multiple phases of inflammation, but is optimal in the initial phase, providing protection from graft-versus-host disease while maintaining the graft-versus-tumor effect even at physiologic doses of Tregs due to their in vivo expansion, hence overcoming a major barrier to potential clinical applications of Tregs given their rarity.
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Gardell, Jennifer, Daniel Boster, Justin Bowser, Courtney Crane, Rachael Fasnacht, Kristin Fitzpatrick, Gleda Hermansky, et al. "A NOVEL BISPECIFIC CD8 TREG MODULATOR TARGETING CYTOLYTIC CD8 REGULATORY T CELLS REDUCES PATHOGENIC CD4 T CELLS AND INFLAMMATION IN TRANSLATIONAL MODELS OF INTESTINAL AUTOIMMUNE AND INFLAMMATORY DISEASE." Inflammatory Bowel Diseases 29, Supplement_1 (January 26, 2023): S12. http://dx.doi.org/10.1093/ibd/izac247.024.
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Abstract INTRODUCTION We have characterized a novel CD8 Treg network in autoimmune patient peripheral blood and tissues, in which a subset of cytolytic CD8 Treg eliminate pathogenic CD4 T cells, reducing inflammation and ameliorating disease in response to pathogenic CD4 T cell activation. We hypothesize that the CD8 Treg network is dysfunctional in patients with Celiac and Crohn’s disease, allowing pathogenic CD4 T cell expansion, the initiation of a cascade of inflammatory pathological consequences and the perpetuation of tissue destructive inflammation in Celiac disease and IBD. Here we demonstrate the use of bispecific CD8 Treg modulators that may have the potential to restore the elimination of pathogenic CD4 T cells in disease. METHODS CD8 Treg were cultured with autologous antigen presenting cells pulsed with gliadin peptides, and either primary autologous CD4 T cells or a target gliadin-responsive T cell line. Novel bispecific CD8 Treg Modulators were designed and evaluated for targeted binding by Octet and flow cytometry. The functional impact of CD8 Treg modulators was evaluated using flow cytometry, Incucyte, and supernatant analysis in PBMCs isolated from Celiac and Crohn’s disease patients. CD8 Treg Modulators were also tested using celiac patient duodenal tissue biopsies and in xenograft animal models of acute GVHD. RESULTS Activation of human CD8 Treg resulted in rapid cytolysis of pathogenic CD4 T cells as one mechanism of action. Upon the addition of CD8 Treg modulators, activation, and prevalence of CD8 Tregs increased along with the increase of degranulation and lytic molecules, and the death of antigen activated CD4 T cells. Following gliadin exposure of intestinal organoid cultures, in the presence of CD8 Treg modulators, CD8 Treg prevalence increased, coincident with the reduction of activated CD4 T cell and a decrease of epithelial cell death. The administration of CD8 Treg modulators in a humanized mouse model of acute graft versus host disease resulted in delayed onset and decreased severity of disease (based on clinical score and tissue pathology), and reduction of pro-inflammatory serum cytokines. CONCLUSION Our results indicate that CD8 Treg modulators activate CD8 Tregs in vitro, in vivo, and in human tissue resulting in decreased inflammation and amelioration of disease. Our data suggest that this network can be targeted by immune-modulating biologics to suppress pathogenic T cells to reduce disease severity & delay onset, as well as mitigate severity & frequency of flares in patients with Celiac disease and IBD. Figure 1. CD8 regulatory T cells (CD8 Treg) fail to eliminate pathogenic CD4 T cells in autoimmune disorders. CD8 Treg are responsible for eliminating pathogenic CD4 T cells when they become activated in response to an antigenic trigger. When successful, pathogenic CD4 T cells are eliminated, preventing their expansion and downstream inflammatory consequences, including plasmablast activation and autoantibody secretion, production of pro-inflammatory cytokines and chemokines, recruitment of inflammatory immune cells and bystander T cell activation. In autoimmunity, this surveillance process fails, resulting in inflammation and tissue damage. Figure 2. Mozart’s CD8 Treg Modulators delay disease onset and reduce severity of disease in xenograft models of acute GVHD. CD8 Treg, characterized by expression of inhibitory KIR checkpoint proteins, can prevent disease when mobilized (Figure 2A). NSG mice were injected once a week for 4 weeks (ending day 21) with 0.2mg/kg CD8 Treg modulators. Bispecific antibody like molecules directed against KIR and CD8 induce CD8 Treg mobilization in vivo resulting in reduced pathology, proinflammatory serum cytokines, and disease severity (Figure 2B). CD8 Treg modulators also delayed disease onset and enhanced survival (Figure 2C).
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Fan, Xiying, Bruno Moltedo, Alejandra Mendoza, Alexey N. Davydov, Mehlika B. Faire, Linas Mazutis, Roshan Sharma, Dana Pe’er, Dmitriy M. Chudakov, and Alexander Y. Rudensky. "CD49b defines functionally mature Treg cells that survey skin and vascular tissues." Journal of Experimental Medicine 215, no. 11 (October 24, 2018): 2796–814. http://dx.doi.org/10.1084/jem.20181442.
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Regulatory T (Treg) cells prevent autoimmunity by limiting immune responses and inflammation in the secondary lymphoid organs and nonlymphoid tissues. While unique subsets of Treg cells have been described in some nonlymphoid tissues, their relationship to Treg cells in secondary lymphoid organs and circulation remains unclear. Furthermore, it is possible that Treg cells from similar tissue types share largely similar properties. We have identified a short-lived effector Treg cell subset that expresses the α2 integrin, CD49b, and exhibits a unique tissue distribution, being abundant in peripheral blood, vasculature, skin, and skin-draining lymph nodes, but uncommon in the intestines and in viscera-draining lymph nodes. CD49b+ Treg cells, which display superior functionality revealed by in vitro and in vivo assays, appear to develop after multiple rounds of cell division and TCR-dependent activation. Accordingly, single-cell RNA-seq analysis placed these cells at the apex of the Treg developmental trajectory. These results shed light on the identity and development of a functionally potent subset of mature effector Treg cells that recirculate through and survey peripheral tissues.
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Smith, Alan J., Dharti Shantaram, Joey Liu, Valerie P. Wright, David Bradley, and Willa A. Hsueh. "Peroxisome proliferator-activated receptor gamma activation reverses adipose tissue regulatory T cell dysfunction." Journal of Immunology 206, no. 1_Supplement (May 1, 2021): 113.12. http://dx.doi.org/10.4049/jimmunol.206.supp.113.12.
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Abstract Adipose tissue (AT) regulatory T Cells (Tregs) play an essential role in regulating inflammatory and metabolic responses. Obesity is associated with a decrease in AT Tregs and a corresponding increase in tissue inflammation and systemic insulin resistance in both humans and mice. In human samples, we have found Tregs isolated from visceral AT (VAT) display a dysfunctional phenotype characterized by decreased viability, decreased effector function, and increased expression of inhibitory co-receptors (PD-1 and OX40). VAT Tregs cultured with peripheral blood mononuclear cells (PBMCs) display reduced ability to suppress proliferation, while peripheral blood Tregs suppress proliferation normally. As peroxisome proliferator-activated receptor (PPAR)-gamma has been shown to be a regulator of AT Tregs, we hypothesize that the Treg dysfunction can be reversed by addition of the PPAR-gamma agonist Pioglitazone. We isolated Tregs from VAT and peripheral blood and added cells to CFSE-labelled PBMCs in the presence and absence of Pioglitazone. After 4 days culture, Pioglitazone was found to significantly improve the ability of VAT Tregs to suppress proliferation. This effect was specific to AT Treg populations as Pioglitazone alone did not affect PBMC proliferation. These data suggest that Treg dysfunction contributes to AT inflammation and activation of PPAR-gamma promotes VAT-specific Treg activity providing therapeutic implications for PPAR-gamma agonists. (Partially supported by the OSU Cancer Center Support Grant P30CA016058).
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Dürr, Christoph, Dietmar Pfeifer, Annette Schmitt-Gräff, Rainer Claus, Ulrike Gerlach, Ralph Graeser, Armin Gerbitz, Robert Negrin, Jürgen Finke, and Robert Zeiser. "Tissue Damage and Lymphoma Derived Chemoattractive Signals Impact Regulatory T Cell Trafficking After Allogeneic Hematopoietic Cell Transplantation." Blood 114, no. 22 (November 20, 2009): 3564. http://dx.doi.org/10.1182/blood.v114.22.3564.3564.
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Abstract Abstract 3564 Poster Board III-501 Regulatory T cells (Treg) have been shown previously to reduce graft-versus-host disease (GvHD) but allow for graft-versus-leukemia (GvL) effects. It is still unclear why the adoptive Treg transfer does not paralyze every immune response to the same extent. In that context Treg recruitment and localization may account for differential immune regulation. Therefore, we studied the impact of lymphoma and inflammation derived chemoattractive signals on Treg recruitment. Luciferase transgenic Treg accumulated in B cell lymphoma (BCL) tissue after allogeneic hematopoietic cell transplantation (alloHCT) when no conventional T cells were given. Microarray based analysis of the BCL tissue revealed increased expression of the CXC chemokine ligands (CXCL) 9, 10, 12 and CCL22. In vivo antibody based neutralization or interference with receptor signaling identified CCL22 and CXCL12 as critical chemokines for Treg attraction towards BCL tissue after alloHCT. Conversely, the CXCL9/10-CXCR3 axis was not critical for Treg recruitment. Depletion of antigen presenting cells (APC) from BCL tissue abrogated CCL22/CXCL12 secretion. CD11c-DTR recipients displayed reduced Treg recruitment towards BCL, indicative for a major role of host APC in the process of Treg recruitment. Strong local inflammatory stimuli caused by subcutaneous complete Freund's adjuvant injection caused local Treg accumulation and reduced recruitment to the BCL. Infusion of conventional T cells that caused subacute GvHD related inflammation redirected Treg towards secondary lymphoid organs and abdominal GvHD target organs. In conclusion our study demonstrates the following novel findings: First Treg are recruited towards BCL infiltrated tissues after alloHCT and this process is dependent on CCL22 and CXCL12 production. Secondly, BCL infiltrating host type APC are the major source for CCL22 and CXCL12 and their targeted deletion impacts Treg recruitment towards BCL tissue. Thirdly, strong local or systemic inflammation can redirect Treg trafficking in the presence of BCL and affect the accumulation of this cell population at the tumor site which may explain why Treg preferentially regulate GvHD reactions post allografting. Disclosures: No relevant conflicts of interest to declare.
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Barros, Leandro, Cristina Ferreira, and Marc Veldhoen. "The fellowship of regulatory and tissue-resident memory cells." Mucosal Immunology 15, no. 1 (October 4, 2021): 64–73. http://dx.doi.org/10.1038/s41385-021-00456-w.
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AbstractT cells located in non-lymphoid tissues have come to prominence in recent years. CD8+ tissue-resident memory (Trm) cells are important for tissue immune surveillance, provide an important line of defence against invading pathogens and show promise in cancer therapies. These cells differ in phenotype from other memory populations, are adapted to the tissue they home to where they found their cognate antigen and have different metabolic requirements for survival and activation. CD4+ Foxp3+ regulatory T (Treg) cells also consist of specialised populations, found in non-lymphoid tissues, with distinct transcriptional programmes. These cells have equally adapted to function in the tissue they made their home. Both Trm and Treg cells have functions beyond immune defence, involving tissue homeostasis, repair and turnover. They are part of a multicellular communication network. Intriguingly, occupying the same niche, Treg cells are important in the establishment of Trm cells, which may have implications to harness the immune surveillance and tissue homeostasis properties of Trm cells for future therapies.
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Smigiel, Kate, Elizabeth Richards, Kerri Thomas, and Dan Campbell. "CCR7 coordinates paracrine interleukin-2 cross-talk between central memory and regulatory T cells and controls the homeostatic balance between regulatory T cell subsets (P1065)." Journal of Immunology 190, no. 1_Supplement (May 1, 2013): 121.4. http://dx.doi.org/10.4049/jimmunol.190.supp.121.4.
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Abstract The importance of IL-2 in immune suppression mediated by Foxp3+ Treg cells is well established. However, IL-2 is not required for Treg cell development, in vitro suppression, or to maintain total cell number; thus, the mechanism by which IL-2 controls Treg cell activity remains unclear. We demonstrate that CD44lo CD62Lhi lymphoid tissue-resident Treg cells require IL-2 for survival and maintenance, whereas CD44hi CD62Llo Treg cells with a peripheral tissue homing phenotype are IL-2 independent. We termed these subsets central (cTr) and effector Treg (eTr) cells, respectively, due to their unique homeostatic requirements and migratory potential. Furthermore, we show that the chemokine receptor CCR7 provides cTr cells access to IL-2 by coordinating their localization in proximity to IL-2-producing CCR7+ Foxp3- central memory cells in the T cell zones of secondary lymphoid tissues. Collectively, our data demonstrate that the factors governing the homeostasis and maintenance of different Treg cell subsets are highly dependent on their tissue and microenvironment localization and indicate that loss of immune tolerance in the absence of IL-2 or CCR7 is due to an imbalance of cTr and eTr cells.
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Christofi, Panayiota, Chrysoula Pantazi, Nikoleta Psatha, Ioanna Sakellari, Evangelia Yannaki, and Anastasia Papadopoulou. "Promises and Pitfalls of Next-Generation Treg Adoptive Immunotherapy." Cancers 15, no. 24 (December 17, 2023): 5877. http://dx.doi.org/10.3390/cancers15245877.
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Regulatory T cells (Tregs) are fundamental to maintaining immune homeostasis by inhibiting immune responses to self-antigens and preventing the excessive activation of the immune system. Their functions extend beyond immune surveillance and subpopulations of tissue-resident Treg cells can also facilitate tissue repair and homeostasis. The unique ability to regulate aberrant immune responses has generated the concept of harnessing Tregs as a new cellular immunotherapy approach for reshaping undesired immune reactions in autoimmune diseases and allo-responses in transplantation to ultimately re-establish tolerance. However, a number of issues limit the broad clinical applicability of Treg adoptive immunotherapy, including the lack of antigen specificity, heterogeneity within the Treg population, poor persistence, functional Treg impairment in disease states, and in vivo plasticity that results in the loss of suppressive function. Although the early-phase clinical trials of Treg cell therapy have shown the feasibility and tolerability of the approach in several conditions, its efficacy has remained questionable. Leveraging the smart tools and platforms that have been successfully developed for primary T cell engineering in cancer, the field has now shifted towards “next-generation” adoptive Treg immunotherapy, where genetically modified Treg products with improved characteristics are being generated, as regards antigen specificity, function, persistence, and immunogenicity. Here, we review the state of the art on Treg adoptive immunotherapy and progress beyond it, while critically evaluating the hurdles and opportunities towards the materialization of Tregs as a living drug therapy for various inflammation states and the broad clinical translation of Treg therapeutics.
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Jacob, Jacinta, Alessia Volpe, Qi Peng, Robert I. Lechler, Lesley A. Smyth, Giovanna Lombardi, and Gilbert O. Fruhwirth. "Radiolabelling of Polyclonally Expanded Human Regulatory T Cells (Treg) with 89Zr-oxine for Medium-Term In Vivo Cell Tracking." Molecules 28, no. 3 (February 3, 2023): 1482. http://dx.doi.org/10.3390/molecules28031482.
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Regulatory T cells (Tregs) are a promising candidate cell therapy to treat autoimmune diseases and aid the longevity of transplanted solid organs. Despite increasing numbers of clinical trials using human Treg therapy, important questions pertaining to their in vivo fate, distribution, and function remain unanswered. Treg accumulation in relevant tissues was found to be crucial for Treg therapy efficacy, but existing blood-borne biomarkers are unlikely to accurately reflect the tissue state. Non-invasive Treg tracking by whole-body imaging is a promising alternative and can be achieved by direct radiolabelling of Tregs and following the radiolabelled cells with positron emission tomography (PET). Our goal was to evaluate the radiolabelling of polyclonal Tregs with 89Zr to permit their in vivo tracking by PET/CT for longer than one week with current preclinical PET instrumentation. We used [89Zr]Zr(oxinate)4 as the cell-labelling agent and achieved successful radiolabelling efficiency of human Tregs spanning 0.1–11.1 Bq 89Zr/Treg cell, which would be compatible with PET tracking beyond one week. We characterized the 89Zr-Tregs, assessing their phenotypes, and found that they were not tolerating these intracellular 89Zr amounts, as they failed to survive or expand in a 89Zr-dose-dependent manner. Even at 0.1 Bq 89Zr per Treg cell, while 89Zr-Tregs remained functional as determined by a five-day-long effector T cell suppression assay, they failed to expand beyond day 3 in vitro. Moreover, PET imaging revealed signs of 89Zr-Treg death after adoptive transfer in vivo. In summary, 89Zr labelling of Tregs at intracellular radioisotope amounts compatible with cell tracking over several weeks did not achieve the desired outcomes, as 89Zr-Tregs failed to expand and survive. Consequently, we conclude that indirect Treg labelling is likely to be the most effective alternative method to satisfy the requirements of this cell tracking scenario.
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Harrison, Ranee, Yair Botbol, Simone Sidoli, Ana-Maria Cuervo, and Fernando Macian. "Chaperone-mediated autophagy modulates regulatory T cell differentiation and function." Journal of Immunology 210, no. 1_Supplement (May 1, 2023): 248.06. http://dx.doi.org/10.4049/jimmunol.210.supp.248.06.
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Abstract Autophagy has been shown to regulate many key functions of the immune system including important roles in effector and memory T cell maintenance and function. Our group showed that chaperone-mediated autophagy (CMA), a selective type of autophagy that declines with age, plays a key role in T cell activation. In this work, we have analyzed the role of CMA in generation and function of regulatory T cells (Tregs). We found that resting Tregs display high basal CMA activity, which further increases upon Treg activation. We generated Treg specific CMA-deficient mice (Foxp3:Cre-LAMP2A fl/fl) and found that they have significantly reduced body weight due to reduced fat mass. We propose that the CMA status of adipose tissue infiltrating Tregs may have a direct impact on adipose tissue inflammation state. In fact, as the Treg-specific CMA-deficient mice age, we found marked inflammation and reduced survival, suggesting a role for CMA in maintaining Treg self-tolerance under homeostatic conditions. We confirmed that CMA-deficient Tregs have reduced suppressive activity in vivo and have identified the Treg sub-proteome regulated by CMA using comparative quantitative proteomic analysis of control and CMA-deficient Tregs. This has allowed us to identify cellular pathways behind the mechanism by which CMA regulates Treg function. The proteomic analysis hits will help in identifying potential targets of CMA that could be used therapeutically to modulate Treg function, to prevent autoimmunity or boost anti-tumor immune responses. Supported by grants from NIH P01-AG031782 R01-AI113919
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Elkins, C., Pulavendran Sivasami, Jennifer Bae, and Chaoran Li. "Cellular cholesterol homeostasis supports visceral adipose tissue (VAT) regulatory T cell (Treg) accumulation and promotes metabolic health." Journal of Immunology 210, no. 1_Supplement (May 1, 2023): 76.16. http://dx.doi.org/10.4049/jimmunol.210.supp.76.16.
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Abstract A unique population of regulatory T cells (Tregs), characterized by a clonally expanded TCR repertoire and distinct transcriptional profile, is highly enriched in the visceral adipose tissue (VAT) at steady state but is lost during obesity, which exacerbates VAT inflammation and promotes metabolic disease. Therefore, understanding the factors that control the accumulation of VAT Tregs, which might be dysregulated during obesity, is important for developing novel therapies for obesity-associated metabolic diseases. Here we show that cellular cholesterol homeostasis is particularly important for VAT Treg accumulation and function. First, bulk RNA sequencing analysis of VAT Tregs from mice fed long-term high fat diet (HFD) showed a reduction in gene expression involved in cholesterol homeostasis (CH), corresponding to loss of VAT Tregs in vivo. Second, we found that VAT Tregs showed increased cholesterol-associated gene expression, cholesterol levels, and cholesterol uptake compared to lymphoid Tregs at steady state, suggesting this pathway is particularly important for VAT Tregs. Third, CRISPR-Cas9-mediated ablation of Srebf2, the master regulator of cholesterol homeostasis, followed by adoptive Treg transfer or Treg-specific germline deletion of Srebf2(Foxp3cre Srebf2-flox) reduced Tregs in the VAT, but not those in other tissues. Deletion of Srebf2in Tregs also increased VAT inflammatory cytokine expression, inflammatory cell infiltration, and insulin resistance in mice following short-term HFD feeding. These data highlight an importance of cellular CH for VAT Treg accumulation and function and implicate this pathway as a potential therapeutic target for treatment of obesity-associated metabolic diseases. NIH R01 (5R01DK128061-02)
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Ho, Patrick, Jeffrey A. Bluestone, and Qizhi Tang. "Elucidating Inflammation-induced Cell Fate Decisions in Primary Human Tregs." Journal of Immunology 210, no. 1_Supplement (May 1, 2023): 238.01. http://dx.doi.org/10.4049/jimmunol.210.supp.238.01.
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Abstract Adoptive regulatory T-cell (Treg) therapy is an emerging therapeutic paradigm for promoting immune tolerance in transplant and autoimmune disease settings. Prior investigations demonstrate that murine Tregs can undergo epigenetic reprogramming within chronically inflamed tissue environments, resulting in acquisition of proinflammatory functions and the capacity to exacerbate tissue damage. Despite the ramifications of Treg lineage decommitment for cell therapy applications, inflammation-induced human Treg cell fate decisions remain poorly understood. Here, we present a robust in vitromodel of IL6, IL1β, and IL23-driven Treg instability characterized by progressive FOXP3 and HELIOS downregulation, FOXP3conserved non-coding sequence (CNS)2 enhancer re-methylation, diminished in vitrosuppressive function, and elevated proinflammatory cytokine expression. To gain insight into the gene regulatory networks enabling the loss of Treg identity, we generated single-cell transcriptomic and chromatin accessibility profiles of primary human Tregs maintained in the presence or absence of IL6, IL1β, and IL23. Unsupervised clustering revealed a dysfunctional Treg population with an epigenetic signature consistent with murine Treg to “exTreg” conversion, including altered chromatin accessibility at the IFNγ, IL17A, and FOXP3CNS2 loci. Inference of transcription factor (TF)-associated changes in chromatin accessibility indicated a key role for E26 transformation-specific (ETS) family members. Ongoing experiments aim to identify specific TF modules that can be targeted to better safeguard the function and stability of Treg therapeutics.
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Beppu, Lisa, Adolfo Frias, Eric Hyzny, Amanda Poholek, and Louise D’Cruz. "The role of Blimp-1 in adipose Treg differentiation and effector function." Journal of Immunology 202, no. 1_Supplement (May 1, 2019): 128.11. http://dx.doi.org/10.4049/jimmunol.202.supp.128.11.
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Abstract Visceral adipose tissue regulatory T cells (VAT Tregs) protect against systemic inflammation and metabolic disease by limiting expansion of pro-inflammatory Th1 cells and M1 macrophages, and by preserving insulin sensitivity and glucose tolerance. Although their basic markers and roles have been studied, less is known about the transcriptional machinery regulating their differentiation and function. B lymphocyte-induced maturation protein-1 (BLIMP-1) is a transcriptional regulator known to be involved in the development, polarization, and maintenance of various immune cells including CD4+ T cells. Using BLIMP-1 reporter mice, we have discovered that BLIMP-1 is constitutively expressed in a subset of VAT Tregs compared to lymphoid Tregs, and that BLIMP-1+ VAT Tregs are phenotypically distinct from their BLIMP-1-counterparts. Blimp-1 is not required for VAT Treg development, however Treg-specific deletion of BLIMP-1 led to unique changes in VAT Treg markers in lean versus obese adipose tissue. Based on these preliminary data, our project aims to elucidate the role of BLIMP-1 in shaping the VAT Treg compartment and to explore a possible role for BLIMP-1+ VAT Tregs in metabolic co-morbidities such as obesity and Type II diabetes.
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Valle, Jose, Jovanny Guillen, Sarah DiMichele, Mariela Pauli, Corey Tan, Caroline Lam, Claudia X. Dominguez, et al. "In silico and multi-dimensional functional interrogation of tissue Tregs reveals novel therapeutics for autoimmunity and inflammation." Journal of Immunology 210, no. 1_Supplement (May 1, 2023): 234.15. http://dx.doi.org/10.4049/jimmunol.210.supp.234.15.
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Abstract Many inflammatory and autoimmune diseases present with specific organ manifestations. Understanding the immune process at the site of inflammation may offer important insights into novel therapeutic strategies. To this end, we established a biology platform that allows us to develop a deep understanding of human tissue Treg behavior to enable a next generation of therapeutics aimed at activating these regulatory circuits at the location where the disease manifests. We apply single-cell RNA sequencing and computational tools to our proprietary collection of healthy and diseased tissues to generate a high-resolution map of immune-regulatory pathways. Based on these learnings, we established in vitro culturing conditions that induce the expression of these tissue pathways in primary human Treg. Lastly, we have developed a suite of disease relevant phenotypic assays that allows for multi-dimensional functional interrogation of the mapped tissue Treg pathways in our in vitro-conditioned human primary Treg. This combination of complex in silico tools and translational in vitro assays allows us to identify novel regulatory nodes and forms the foundation of our growing pipeline of a new class of tissue Treg-focused therapeutics for immune-mediated diseases.
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Köhne, Maren, and Marc Beyer. "ATAC-ing human tissue Treg cells." Immunity 54, no. 4 (April 2021): 605–7. http://dx.doi.org/10.1016/j.immuni.2021.03.014.
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Thornton, Angela M., Oksana F. Gavrilova, Vinay R. Penna, Patricia E. Korty, and Ethan M. Shevach. "A Treg-specific deletion of Helios causes autoimmune lipodystrophy and metabolic syndrome." Journal of Immunology 202, no. 1_Supplement (May 1, 2019): 116.13. http://dx.doi.org/10.4049/jimmunol.202.supp.116.13.
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Abstract Regulatory T (Treg) cells suppress immune activation in a dominant manner and play a critical role in the maintenance of self-tolerance. A subpopulation (60–75%) of Foxp3+T regulatory (Treg) cells express the transcription factor Helios. To examine the function of Helios in Treg cells, we have generated Treg-specific Helios deficient mice (cKO, Heliosflxflx Foxp3cre). Although both Treg development in the cKO mice and their in vitro suppressor function are normal, the selective deletion of Helios in Tregs leads to slow, progressive systemic immune activation with a Th1 phenotype, hypergammaglobulinemia, and enhanced germinal center formation. Initially, we observed significant lymphocytic infiltrates only in the salivary gland and not in any other organs typically affected by Treg dysregulation. Strikingly, the mice developed lipodystrophy, hepatic steotosis and insulin resistance. Further analysis revealed a significant lymphocytic infiltrate in both the inguinal and perigonadal adipose tissue, indicating autoimmune mediated destruction of the white adipose tissue (WAT). We have further shown that the lymphocytic infiltrate specific to WAT can be transferred from mice with lipodystrophy to immunodeficient mice, confirming the autoimmune nature of the lipodystrophy. Thus, Helios deficiency in Treg disrupts immune homeostasis in the adipose tissue, leading to the destruction of WAT and redirection of lipids to the liver, and ultimately causes metabolic dysfunction. Supported by the Intramural Research Program of the NIAID, NIH.
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Beppu, Lisa, Xiaoyao Qu, Giovanni Marrero, Allen Fooks, Adolfo Frias, Katherine Helfrich, Ian Sipula, et al. "Blimp-1 in adipose resident Tregs controls adipocyte beiging and obesity." Journal of Immunology 204, no. 1_Supplement (May 1, 2020): 81.9. http://dx.doi.org/10.4049/jimmunol.204.supp.81.9.
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Abstract Visceral adipose tissue regulatory T cells (VAT Tregs) protect against systemic inflammation and metabolic disease by limiting expansion of pro-inflammatory Th1 cells and M1 macrophages, and by preserving insulin sensitivity and glucose tolerance. Although their basic markers and roles have been studied, less is known about the transcriptional machinery regulating their differentiation and function. B lymphocyte-induced maturation protein-1 (Blimp-1) is a transcriptional regulator known to be involved in the development, polarization, and maintenance of various immune cells including CD4+ T cells. Using Blimp-1 reporter mice, we discovered that Blimp-1 is constitutively expressed in a subset of VAT Tregs compared to lymphoid Tregs, and that Blimp-1+ VAT Tregs are phenotypically distinct from their Blimp-1− counterparts. Blimp-1 is not required for VAT Treg development, however Treg-specific deletion of Blimp-1 led to unique changes in VAT Treg markers in lean versus obese adipose tissue. In addition, Blimp-1 knockout mice fed high fat diet had fewer adipose-resident NK cells and increased CD8 T cells. Surprisingly, loss of Blimp-1+ Tregs led to less adipose tissue IL-10, increased expression of thermogenic genes, reduced body fat, decreased weight, and improved insulin sensitivity. Based on these data, we hypothesize that Blimp-1+ Treg dependent IL-10 production suppresses adipocyte beiging, and that loss of these cells results in increased thermogenesis, greater weight loss and improved insulin sensitivity in obese mice.
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Tomura, Michio, Ryoyo Ikebuchi, Shunsuke Teraguchi, Alexis Vandenbon, Shand H. W. Francis, and Tetsuya Honda. "A rare subset of skin-tropic regulatory T cells expressing Il10/Gzmb inhibits the cutaneous immune response." Journal of Immunology 198, no. 1_Supplement (May 1, 2017): 206.14. http://dx.doi.org/10.4049/jimmunol.198.supp.206.14.
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Abstract We reported that Foxp3+ regulatory T cells (Tregs) migrating from the skin to the draining lymph node have a strong immunosuppressive effect on contact hypersensitivity (CHS) response. However, the Treg subsets that regulate the CHS response remain poorly defined. In this study, we used a combination of single-cell real-time PCR high-dimensional gene expression profiling data with spatiotemporal information about cellular movement from the mice expressing the photoconvertible protein KikGR to elucidate the role and characteristics of Treg subsets in CHS response. We found that although immunosuppressive genes Ctla4 and Tgfb1 were expressed in the majority of Tregs, Il10-expressing Tregs were rare and unexpectedly, the majority of Il10-expressing Tregs co-expressed Gzmb and displayed Th1-skewing. Furthermore, Gzmb-/Il10-expressing Treg subsets expressed the novel markers CD43 and CCR5. CD43+ CCR5+ CXCR3− Tregs highly expressed skin-tropic chemokine receptors CCR4 and CCR8. We also measured the retention of Treg subsets within inflamed skin using KikGR mice, and found that the subset of Tregs that was most highly retained in the skin, CD43+ CCR5+ CXCR3− Tregs, had superior in vivo inhibitory function to other Treg subsets. These results suggested that even if only present in small numbers, highly activated Tregs that co-express Gzmb and Il10 and that have the capacity to remain in inflamed tissue are likely to be clinically relevant due to the role of these molecules in the control of excessive immune responses. Taken together, the identification of a rare Treg subset co-expressing multiple immunosuppressive molecules and having tissue-remaining capacity offers a novel strategy for the control of skin inflammatory responses.
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Liu, Quan, Jeremy M. Lott, Lisa R. Mathews, Huihua Li, Qiang Zhu, Benjamin M. Matta, Greg M. Delgoffe, Ming-Hui Fan, and Heth R. Turnquist. "IL-33-Driven Innate Tissue-Protective Function of ST2+ Treg Cells." Journal of Immunology 196, no. 1_Supplement (May 1, 2016): 51.7. http://dx.doi.org/10.4049/jimmunol.196.supp.51.7.
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Abstract Non-lymphoid tissue-resident CD4+ Foxp3+ regulatory T (Treg) cells with the capacity to modulate non-immunological processes including organismal metabolism and tissue repair have been recently described. Notably, a large fraction of non-lymphoid tissue-resident Treg cells express ST2, the receptor for the tissue-derived cytokine and alarmin, IL-33. However, the relationship between IL-33 and ST2+ Treg cells in quiescent and pathogenic states is only starting to be understood. Using FACS and Foxp3 reporter mice, we demonstrate that ST2+ Treg cells from naïve animals are phenotypically and functionally unique relative to ST2− Treg isolated from the same location. Yet, our studies establish that peripheral and lymphoid tissue ST2+ Treg cells are highly comparable. Interestingly, ST2+ Treg exhibit a high level of aerobic glycolysis, which supports their augmented potential for cytokine secretion, especially that of IL-5, IL-10, and IL-13. IL-5 and IL-13 secretion in response to IL-33 is an innate function of ST2+ Treg cells as it does not require TCR-stimulation. Conversely, ST2+ Treg release of other cytokines, including IL-10, is antigen-restricted and amplified by IL-33. Among Treg subsets, ST2+ Treg cells are the exclusive source of Type 2 cytokines, especially IL-13, which we reveal supports Treg reparative responses. Using mice deficient in IL-33 or Treg cells, we establish that Treg cells and IL-33 are both required to protect mice from lethal lung injury. In line with these data, delivery of IL-13, but not IL-33, at the time of lung injury rescues Treg-depleted mice. This study establishes that ST2+ Treg cells possess an innate capacity for cytokine production that is crucial to tissue repair and inflammation control.
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Fisher, James D., Stephen C. Balmert, Wensheng Zhang, Riccardo Schweizer, Jonas T. Schnider, Chiaki Komatsu, Liwei Dong, et al. "Treg-inducing microparticles promote donor-specific tolerance in experimental vascularized composite allotransplantation." Proceedings of the National Academy of Sciences 116, no. 51 (December 2, 2019): 25784–89. http://dx.doi.org/10.1073/pnas.1910701116.
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For individuals who sustain devastating composite tissue loss, vascularized composite allotransplantation (VCA; e.g., hand and face transplantation) has the potential to restore appearance and function of the damaged tissues. As with solid organ transplantation, however, rejection must be controlled by multidrug systemic immunosuppression with substantial side effects. As an alternative therapeutic approach inspired by natural mechanisms the body uses to control inflammation, we developed a system to enrich regulatory T cells (Tregs) in an allograft. Microparticles were engineered to sustainably release TGF-β1, IL-2, and rapamycin, to induce Treg differentiation from naïve T cells. In a rat hindlimb VCA model, local administration of this Treg-inducing system, referred to as TRI-MP, prolonged allograft survival indefinitely without long-term systemic immunosuppression. TRI-MP treatment reduced expression of inflammatory mediators and enhanced expression of Treg-associated cytokines in allograft tissue. TRI-MP also enriched Treg and reduced inflammatory Th1 populations in allograft draining lymph nodes. This local immunotherapy imparted systemic donor-specific tolerance in otherwise immunocompetent rats, as evidenced by acceptance of secondary skin grafts from the hindlimb donor strain and rejection of skin grafts from a third-party donor strain. Ultimately, this therapeutic approach may reduce, or even eliminate, the need for systemic immunosuppression in VCA or solid organ transplantation.
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Broady, Raewyn, Sarah Q. Crome, Jessie Yu, Jan P. Dutz, and Megan K. Levings. "Development of a Modified Skin Explant Assay to Study Treg Suppression of Th17 Cell Mediated GvHD in the Skin." Blood 112, no. 11 (November 16, 2008): 5434. http://dx.doi.org/10.1182/blood.v112.11.5434.5434.
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Abstract Acute graft versus host disease (aGVHD) following haematopoietic stem cell transplantation (HCT) occurs when donor T cells infused with the graft recognise and react to histo-incompatible recipient antigens causing tissue damage. Historically, the inflammatory response in aGVHD was attributed to alloreactive CD4+ T helper and CD8+ cytotoxic T cells and alterations in cytokine production. Recently, a new CD4+ T cell subset, characterised by IL-17 production has been identified. TH17 cells produce high levels of proinflammatory cytokines, including IL-17A, IL-17F, and IL-22, and have been implicated in solid organ rejection and more recently a number of murine studies suggest that Th17 cells play a role in the development of aGVHD. It is well known that FOXP3+ regulatory T cells (Tregs) are critical for the maintenance of self-tolerance, and control the immune response to alloantigens. Murine studies have shown that adoptive transfer of these cells can prevent acute GVHD whereas selective depletion leads to an increased severity. In humans, Tregs also appear to control acute GVHD as they occur at a lower frequency in the peripheral blood patients with aGVHD compared to patients without GVHD. These findings have led to active interest into the use of these cells to prevent or decrease GVHD following allogeneic HCT. It has been reported that in vitro, Th17 cells are resistant to Treg cell mediated suppression of proliferation and IL-17 production, suggesting that the effector functions of Th17 cells might not be susceptible to Treg-cell-mediated inhibition. If true, this would suggest that Treg-based therapies might not be effective at limiting Th17-cell-mediated tissue damage. However, there is currently no evidence regarding whether Treg cells affect the phenotype or function of Th17 cells in tissues. Understanding the interactions between suppressive Tregs and pro-inflammatory T effectors in tissues that are targets of aGVHD, such as the skin, is critical to better define the potential of Tregs as adoptive therapy for the prevention or treatment of aGVHD. In order to address this question, we developed two methods to generate human Th17 cells, one based on over-expression of RORC2 and the other on sorting CCR4+CCR6+CD4+ T cells. We found that ectopic expression of RORC induces a cytokine and chemokine receptor profile analogous to in vivo differentiated Th17 cells. Although expression of RORC2 made CD4+ T cells resistant to Treg-cell mediated suppression of proliferation and IL-17 production, production of IFN-g, TNF-a and IL-6 could be suppressed in these Th17-like cells. In order to further delineate the functional consequence of the interaction between Treg and Th17 cells in tissues we developed a modified the human skin explant model that involves culture of 4 mm punch biopsies of skin with ex vivo Th17 cells (CCR4+CCR6+CD4+ T cells), RORC2 transduced CD4+ T cells, or controls, in the presence or absence of Treg and grading the graft-versus-host reactivity (grades I–IV) histopathologically. Preliminary data suggest that Th17 cells cause significant tissue destruction in this skin explant model, and experiments are ongoing to determine whether Treg cells can counteract these effects.
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Ronin, Emilie, Charlotte Pouchy, Maryam Khosravi, Morgane Hilaire, Sylvie Grégoire, Armanda Casrouge, Sahar Kassem, et al. "Tissue-restricted control of established central nervous system autoimmunity by TNF receptor 2–expressing Treg cells." Proceedings of the National Academy of Sciences 118, no. 13 (March 25, 2021): e2014043118. http://dx.doi.org/10.1073/pnas.2014043118.
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CD4+Foxp3+ regulatory T (Treg) cells are central modulators of autoimmune diseases. However, the timing and location of Treg cell–mediated suppression of tissue-specific autoimmunity remain undefined. Here, we addressed these questions by investigating the role of tumor necrosis factor (TNF) receptor 2 (TNFR2) signaling in Treg cells during experimental autoimmune encephalomyelitis (EAE), a model of multiple sclerosis. We found that TNFR2-expressing Treg cells were critical to suppress EAE at peak disease in the central nervous system but had no impact on T cell priming in lymphoid tissues at disease onset. Mechanistically, TNFR2 signaling maintained functional Treg cells with sustained expression of CTLA-4 and Blimp-1, allowing active suppression of pathogenic T cells in the inflamed central nervous system. This late effect of Treg cells was further confirmed by treating mice with TNF and TNFR2 agonists and antagonists. Our findings show that endogenous Treg cells specifically suppress an autoimmune disease by acting in the target tissue during overt inflammation. Moreover, they bring a mechanistic insight to some of the adverse effects of anti-TNF therapy in patients.
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Beppu, Lisa, Raja Gopal Reddy Mooli, Xiaoyao Qu, Giovanni Marrero, Christopher Finley, Allen Fooks, Zackary Mullen, et al. "Tregs facilitate obesity and insulin resistance via a Blimp-1-IL-10 axis." Journal of Immunology 206, no. 1_Supplement (May 1, 2021): 98.01. http://dx.doi.org/10.4049/jimmunol.206.supp.98.01.
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Abstract Adipose-resident Tregs protect against systemic inflammation and metabolic disease by limiting expansion of pro-inflammatory cells, preserving insulin sensitivity and maintaining glucose tolerance. Although their basic markers and roles have been studied, less is known about the transcriptional machinery regulating their differentiation and function. B lymphocyte-induced maturation protein-1 (Blimp-1) is a transcriptional regulator known to be involved in development, polarization, and maintenance of various immune cells including CD4+ T cells. Using Blimp-1 reporter mice, we discovered that Blimp-1 is constitutively expressed in a subset of visceral adipose tissue (VAT) Tregs, and that Blimp-1+ VAT Tregs are phenotypically distinct from their Blimp-1-counterparts. We also found that Treg-specific Blimp-1 deletion led to altered differentiation and function of VAT and inguinal adipose tissue Tregs. Surprisingly, during diet-induced obesity, Blimp-1 Treg deficient mice gained less weight, had reduced body fat percentage, and exhibited improved insulin sensitivity compared to wild type mice. Furthermore, this was accompanied by upregulation of thermogenic genes such as Ucp1, Prdm16 and Dio2 in inguinal adipose tissue, and increased overall fatty acid oxidation. It has previously been shown that IL-10 can induce thermogenesis. Therefore, we repeated these experiments utilizing mice with Treg-specific deletion of IL-10 and found that they phenocopied the Blimp-1 Treg deficient mice. Based on these results, we hypothesize that cross-talk between Tregs and adipocytes via a Blimp-1-IL-10 axis suppresses thermogenesis, and that absence of Blimp-1+ Tregs is metabolically protective during diet-induced obesity.
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Krebs, Christan F., and Oliver M. Steinmetz. "CD4+T Cell Fate in Glomerulonephritis: A Tale of Th1, Th17, and Novel Treg Subtypes." Mediators of Inflammation 2016 (2016): 1–9. http://dx.doi.org/10.1155/2016/5393894.
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Multiple studies have identified CD4+T cells as central players of glomerulonephritis (GN). Cells of the Th1 and Th17 responses cause renal tissue damage, while Tregs mediate protection. Recently, a high degree of plasticity among these T cell lineages was proposed. During inflammation, Th17 cells were shown to have the potential of transdifferentiation into Th1, Th2, or alternatively anti-inflammatory Tr1 cells. Currently available data from studies in GN, however, do not indicate relevant Th17 to Th1 or Th2 conversion, leaving the Th17 cell fate enigmatic. Tregs, on the other hand, were speculated to transdifferentiate into Th17 cells. Again, data from GN do not support this concept. Rather, it seems that previously unrecognized subspecialized effector Treg lineages exist. These include Th1 specific Treg1 as well as Th17 directed Treg17 cells. Furthermore, a bifunctional Treg subpopulation was recently identified in GN, which secrets IL-17 and coexpresses Foxp3 together with the Th17 characteristic transcription factor RORγt. Similarities between these different and highly specialized effector Treg subpopulations with the corresponding T helper effector cell lineages might have resulted in previous misinterpretation as Treg transdifferentiation. In summary, Th17 cells have a relatively stable phenotype during GN, while, in the case of Tregs, currently available data suggest lineage heterogeneity rather than plasticity.
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Larkin, Bridget M., Jyothsna Visweswaraiah, Bilian Li, Komal Pradhan, Michael Rowe, Gaurav Rajani, Celesztina Nagy-Domonkos, et al. "Selective expansion of regulatory T cells by kidney-tethered IL2 mutein." Journal of Immunology 206, no. 1_Supplement (May 1, 2021): 28.20. http://dx.doi.org/10.4049/jimmunol.206.supp.28.20.
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Abstract Regulatory T cells (Treg) play a critical role in maintaining graft tolerance following organ transplantation, and increased numbers of Tregs in solid-tissue grafts such as the kidney are associated with improved graft survival and function. Therapeutic approaches that increase Tregs offer a promising alternative to current standard-of-care treatment consisting of broad-acting immunosuppressants and their attendant side effects. While efforts to expand Tregs ex vivo for infusion into patients have shown promise, they present manufacturing and administration challenges. Low dose (LD) interleukin 2 (IL-2) drives Treg proliferation and function via the heterotrimeric IL-2 receptor expressed on Tregs and has been shown to expand Tregs in vivo, including in the context of transplantation. However, IL-2 can also activate other immune cells including conventional T cells and Natural Killer (NK) cells, which express IL-2Rb/CD122 and IL-2g/CD132, and this could accelerate rejection. We have enhanced IL-2 selectivity for Treg by introducing mutations that increase affinity for CD25 and decrease affinity for CD122/CD132, resulting in Treg specific expansion. Here, we demonstrate that this IL-2 Mutein (IL-2M) can be “tethered” to the kidney via a bifunctional antibody targeting a tubule-specific protein. This kidney-tethered IL-2M maintains Treg selectivity and localizes to the kidney with extended tissue PK. Moreover, in a CD34-NSG mouse model, animals dosed with kidney-tethered IL-2M exhibited prolonged kidney Treg expansion compared to a systemic, non-tethered IL-2M. This approach has the potential to substantially improve kidney graft acceptance while reducing adverse effects and improving patient quality of life.
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Desai, Sweta, Selene Meza-Perez, Mingyong Liu, and Troy D. Randall. "Characterizing the role of IL-33/ST2 axis in regulating anti-tumor function by CD8 T cells during tumor metastasis in the omentum." Journal of Immunology 210, no. 1_Supplement (May 1, 2023): 86.07. http://dx.doi.org/10.4049/jimmunol.210.supp.86.07.
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Abstract The omentum, a visceral adipose tissue, is a frequent site of metastasis for gastric and ovarian cancers. Advanced ovarian cancer almost always metastasizes to the omentum. Currently available therapies do not control tumor growth long-term and there is a frequent recurrence of tumor metastasis. In mice, tumor cells injected intraperitoneally implant in the omentum and grow progressively despite tumor-specific CD8 T cells. The lack of effective immunity is due in part, to rapid Treg recruitment in the omentum, which provides an immunosuppressive environment to support tumor growth. The Tregs in the omentum are a specialized population called visceral adipose tissue associated Tregs (VAT-Tregs). A portion of the omental VAT-associated Tregs express ST2, a receptor for Interleukin-33 (IL-33), suggesting that local IL-33 production may contribute to Treg-mediated suppression in the omentum. We also detected persistent, continuously expanding, tumor-specific CD8 T cells in the omentum. Given that IL-33 can also enhance effector function by CD8 T cells and promote their persistence in the presence of chronic antigen stimulation, we are investigating how IL-33 regulates the balance of Treg-mediated immune-suppression and CD8-mediated tumor cell killing in the context of omental adipose tissue. R01CA216234
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Lee, Stephen A., Nichole L. Corless, and Dean A. Lee. "Differential Expression of VEGF Receptors on Human T Cell Subsets." Blood 112, no. 11 (November 16, 2008): 4906. http://dx.doi.org/10.1182/blood.v112.11.4906.4906.
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Abstract Vascular endothelial growth factors (VEGF) and their receptors (VEGFR) deliver important signals that controlling the angiogenesis of growing, injured, and malignant tissues. Expression of VEGF receptors has been described on a variety of normal and malignant leukocytes, and presumably plays a role in their trafficking to injured tissue. Differential expression of neuropilin-1 (NRP-1) has been described as a marker of regulatory T cells (Treg) in mice, and may be expressed on human thymocytes, but expression on human Tregs has not been confirmed. Moreover, earlier reports of Treg-specific markers in humans were based on the CD4+CD25+ subset, which is not as reliable for Treg identification as it is in mice. We used cell sorting to obtain pure populations of human Tregs (using the more stringent criteria of CD4+CD25+CD125−) and T helper cells (Th) (CD4+CD25−CD127+). We compared expression in these subsets of VEGFR-1, -2, -3, and NRP-1 and -2 using flow cytometry and quantitative RT-PCR, and NRP-1 splice isoforms by RT-PCR using isoform-specific primers. We were not able to identify any NRP-1 expression in Tregs by any of these methods. In contrast, there was marked differential expression of VEGFR-2 (Flk-1) and -3 (Flt-4), both of which exhibited up to 16-fold higher expression in Tregs than in Th. These findings suggest a role for VEGF in recruiting Tregs to sites of tissue growth as a mechanism for blunting potential autoimmunity to neoexpressed antigens, and thus may also explain the accumulation of Tregs in tumors.
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Lui, Jen Bon P., and Thomas R. Malek. "Endogenous IL-33 contributes to Treg expansion induced by IL-2/CD25, a novel IL-2 biologic developed for low-dose IL-2 therapy." Journal of Immunology 204, no. 1_Supplement (May 1, 2020): 237.13. http://dx.doi.org/10.4049/jimmunol.204.supp.237.13.
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Abstract Low-dose IL-2 therapy is being advanced in patients with autoimmunity by its ability to increase Tregs. A drawback of IL-2, however, is its short-half life and potential off-target immuno-stimulatory effects. To circumvent these limitations, we developed a longer-lasting mouse IL-2/CD25 fusion protein with greater selectivity toward Tregs. IL-2/CD25 is more effective than an equivalent amount of IL-2 in controlling diabetes of NOD mice. Furthermore, compared to other tissues, IL-2/CD25 more readily expanded pancreatic Tregs, suggesting a co-factor that acts with IL-2/CD25. We considered IL-33 as a possible candidate as it also promotes Treg expansion. In this regard, low-dose IL-2/CD25 selectively induced the IL-33R (ST2) on NOD pancreatic Tregs. Correspondingly, ST2 was not substantially induced in Tregs with impaired IL-2R signaling. More importantly, IL-33 supported the expansion of wild-type Tregs, but not Tregs with impaired IL-2R signaling. Thus, Treg expansion by IL-33 depends on IL-2. Reciprocally, Treg expansion in the pancreas by IL-2/CD25 required IL-33 because this expansion was suboptimal in IL-33-deficient B6 mice but was maximal when IL-33 was sequentially administered with IL-2/CD25. However, IL-2/CD25 and IL-33 did not act synergistically for Treg expansion in the pancreas of NOD mice, as IL-33 or IL-2/CD25 were similarly effective individually. This result may reflect that other inflammatory mediators or co-factors associated with the NOD pancreas also influence the Treg response to IL-2/CD25 and IL-33. Overall, these data indicate that tissue-derived IL-33 may contribute to the overall outcome of low-dose IL-2 therapy by supporting Treg expansion during therapy of autoimmune diseases.
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Thornton, Angela M., Vinay Penna, Oksana Gavrilova, and Ethan M. Shevach. "Acquired Lipodystrophy is Mediated by a Treg Specific Deletion of Helios." Journal of Immunology 210, no. 1_Supplement (May 1, 2023): 77.04. http://dx.doi.org/10.4049/jimmunol.210.supp.77.04.
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Abstract The selective deletion of the transcription factor, Helios, in Regulatory T Cells (Treg) leads to systemic immune activation characterized by a Th1 phenotype, hypergammaglobulinemia, and enhanced germinal center formation. Strikingly, we also observe acquired lipodystrophy, hepatic steatosis, and insulin resistance. Further analysis of the lipodystrophy had revealed a significant lymphocytic infiltrate in both the inguinal and perigonadal adipose tissue, indicating autoimmune mediated destruction of the white adipose tissue (WAT). We show here that the destruction of adipocytes is dependent on CD8 +T cells, as Helios fl/fl× Foxp3Cre mice crossed to B2m deficient mice (lacking Class I MHC) maintain normal adipose tissue volume. Flow cytometry analysis of the infiltrate demonstrates that the destruction of the adipose tissue is mediated by CD8 +T cells through both cytotoxic and Fas-L dependent mechanisms. Preliminary analysis of the adipose tissue Tregs suggests that the Treg fail to acquire or maintain an effector state in the absence of Helios. Thus, Helios deficiency in Treg disrupts immune homeostasis in the adipose tissue, leading to the expansion and activation of CD8 +T cells, the destruction of the tissue and metabolic disease. This work was supported by the Intramural Research Program of NIAID, NIH. This work was supported by the Intramural Research Program of NIAID, NIH.
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Tung, Kenneth S. K., Dominik Lenart, Agata Litwinowicz, Jessica Harakal, and Hui Qiao. "Ontogeny of tissue autoantigen expression influences the mechanism of tolerance by Foxp3+ regulatory T cells." Journal of Immunology 198, no. 1_Supplement (May 1, 2017): 149.22. http://dx.doi.org/10.4049/jimmunol.198.supp.149.22.
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Abstract We studied the ontogeny of organ-specific antigen expression and its effects on inducing tolerogenic regulatory T cells (Treg). Autoimmune ovarian disease (AOD) occurred in B6AF1-AIRE null mice, associated with antibody responses to the oocyte antigen NALP5 (syn. MATER) but not zona pellucida 3 (ZP3). Between postnatal days 1 and 2, numerous ovarian ZP3- primary oocytes undergo apoptosis, providing antigens to maintain tolerance to NALP5. Although ZP3 tolerance is AIRE-independent, transient Treg-depleted adult B6AF1-DEREG mice developed AOD and autoantibody responses to both ZP3 and NALP5. To investigate the origin of ZP3-specific Tregs, we examined the ontogeny of autoantibody responses after Treg depletion. Unlike adult mice, juvenile mice with Treg depletion from postnatal days 5 to 13 developed AOD and produced autoantibodies to NALP5 but not ZP3. In addition, juvenile AOD was Th1-dominant and adult AOD was Th2-dominant. The conversion from Th1 to Th2 was evidenced by the emergence of an IgG1+ ZP3 autoantibody response after Treg depletion on postnatal day 23, nine days after the onset of physiological follicular atresia occurring on postnatal day 14. Follicular atresia accompanies normal estrus in ~80% of growing oocytes, involving granulosa cell apoptosis and removal of dead ZP3+NALP5+ oocytes by antigen presenting cells. We conclude that ZP3-specific Treg development is a late event occurring beyond the neonatal period; and it likely occurs outside the thymus in response to ovarian ZP3 derived from the estrus cycle. Therefore, the ontogeny of tissue autoantigen exposure in an internal organ can regulate the induction of Treg-dependent tolerance to organ-specific antigens.
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Swatler, Julian, Marco De Luca, Ivano Rotella, Veronica Lise, Emilia Maria Cristina Mazza, and Enrico Lugli. "CD4+ Regulatory T Cells in Human Cancer: Subsets, Origin, and Molecular Regulation." Cancer Immunology Research 12, no. 4 (April 2, 2024): 393–99. http://dx.doi.org/10.1158/2326-6066.cir-23-0517.
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Abstract CD4+CD25hiFOXP3+ regulatory T cells (Treg) play major roles in the maintenance of immune tolerance, prevention of inflammation, and tissue homeostasis and repair. In contrast with these beneficial roles, Tregs are abundant in virtually all tumors and have been mechanistically linked to disease progression, metastases development, and therapy resistance. Tregs are thus recognized as a major target for cancer immunotherapy. Compared with other sites in the body, tumors harbor hyperactivated Treg subsets whose molecular characteristics are only beginning to be elucidated. Here, we describe current knowledge of intratumoral Tregs and discuss their potential cellular and tissue origin. Furthermore, we describe currently recognized molecular regulators that drive differentiation and maintenance of Tregs in cancer, with a special focus on those signals regulating their chronic immune activation, with relevant implications for cancer progression and therapy.
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Jing, Yi, Yuelin Kong, Denise Trout, Matthew L. Bettini, and Maria Bettini. "Insulin specific TCR repertoire analysis reveals functional diversity of Treg TCRs." Journal of Immunology 208, no. 1_Supplement (May 1, 2022): 104.04. http://dx.doi.org/10.4049/jimmunol.208.supp.104.04.
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Abstract Regulatory T cells (Tregs) are critical in preventing autoimmunity and express a unique TCR repertoire with high affinity to self-antigens. However, whether Treg and effector T cell (Teff) TCR repertoires are similarly divergent in the context of autoimmunity, and whether Tregs are able to maintain TCR affinity advantage has not been clearly defined. Insulin tetramer positive Tregs isolated from pancreatic islets of NOD mice showed a higher level of self-reactivity (CD5) and TCR signaling (Nur77-GFP) than Teffs specific to the same epitope. We isolated and sequenced insulin tetramer+ Teffs and Tregs from islets of NOD mice expressing a fixed TCRα of an insulin specific TCR. Surprisingly, significant overlap was identified between Treg and Teff TCR repertoires, suggesting that similar TCRs can support autoimmune Treg and Teff development and recruitment into the autoimmune response. Both Tregs and Teffs exhibited TCRs with a broad range of reactivity to insulin epitope and Treg TCRs did not show increased reactivity. The disconnect between Nur77-GFP and TCR functional affinity suggests a Treg cell-intrinsic capacity to compete for antigen or to enhance downstream signaling. When re-expressed in vivo using the TCR retrogenic method, Treg derived TCRs showed lower Treg generation and collectively higher diabetogenicity. With comparable Treg generation, low affinity Treg TCR showed significantly lower protection against diabetes than high affinity Treg TCR. These findings indicate that in tissue specific autoimmunity Tregs can express a TCR repertoire with a broad range of functionality and have significant overlap with Teffs of the same specificity, which might negatively affect their suppressive capacity. This work was supported by the NIH (AI125301-01A1) and The Robert and Janice McNair Foundation.
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Szeponik, Louis, Paulina Akeus, Marianne Quiding Järbrink, and William Carl Ivar Rodin. "Regulatory T cells suppress the cytotoxic phenotype of T cells in intestinal tumors of APCMin/+ mice." Journal of Immunology 202, no. 1_Supplement (May 1, 2019): 138.14. http://dx.doi.org/10.4049/jimmunol.202.supp.138.14.
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Abstract The presence of activated T cells in colorectal cancer (CRC) tissues is a strong predictor of patient survival. Our previous research have shown that regulatory T cells (Treg) are able to reduce T-cell transendothelial migration in vitro and accumulation of effector T cells in intestinal tumors in vivo in a murine model for intestinal adenomas (APCMin/+). In this study we investigated the effect of Treg depletion on the cytotoxic potential of conventional αβ T cells and γδ T cells in intestinal adenomas. We used the APCMin/+ \DEREG mouse model, which harbours a high affinity diphtheria toxin receptor under the control of the FOXP3 promoter, to deplete Treg in tumor bearing mice. We found that the number of CD8αβ T cells per mg tissue in the lamina propria was significantly increased in the Treg depleted intestinal adenomas in comparison to the non-depleted tumors. We could confirm this finding with IHC staining in tissue sections. The number of CD8αα T cells and γδ T cells remained unchanged. Furthermore, ex vivo frequencies in the lamina propria of Granzyme B+ CD8αβ T cells were increased in the Treg depleted intestinal adenomas. Following in vitro stimulation of lymphocytes from lamina propria with PMA/ionomycin, there was a trend towards a higher frequency of IFNγ+ CD8αβ T cells in Treg depleted adenomas, but frequencies of CD107a+ CD8αβ T cells were decreased. The frequency of TNF+CD8αβ T cells was elevated in the tumor in comparison to the unaffected tissue regardless of Treg depletion. We are investigating the combined effect of Treg depletion and PD-1 immunotherapy on the cytotoxic phenotype of T cells in the intestinal adenomas. The results indicate that the modulation of Treg in colorectal cancer could have apositive effect on T cell cytotoxicity.
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Kalekar, Lokesh A., Jarish N. Cohen, Nicolas Prevel, Priscila Muñoz Sandoval, Anubhav N. Mathur, Joshua M. Moreau, Margaret M. Lowe, et al. "Regulatory T cells in skin are uniquely poised to suppress profibrotic immune responses." Science Immunology 4, no. 39 (September 6, 2019): eaaw2910. http://dx.doi.org/10.1126/sciimmunol.aaw2910.
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At the center of fibrosing diseases is the aberrant activation of tissue fibroblasts. The cellular and molecular mechanisms of how the immune system augments fibroblast activation have been described; however, little is known about how the immune system controls fibroblast function in tissues. Here, we identify regulatory T cells (Tregs) as important regulators of fibroblast activation in skin. Bulk cell and single-cell analysis of Tregs in murine skin and lungs revealed that Tregs in skin are transcriptionally distinct and skewed toward T helper 2 (TH2) differentiation. When compared with Tregs in lung, skin Tregs preferentially expressed high levels of GATA3, the master TH2 transcription factor. Genes regulated by GATA3 were highly enriched in skin “TH2 Treg” subsets. In functional experiments, Treg depletion resulted in a preferential increase in TH2 cytokine production in skin. Both acute depletion and chronic reduction of Tregs resulted in spontaneous skin fibroblast activation, profibrotic gene expression, and dermal fibrosis, all of which were exacerbated in a bleomycin-induced murine model of skin sclerosis. Lineage-specific deletion of Gata3 in Tregs resulted in an exacerbation of TH2 cytokine secretion that was preferential to skin, resulting in enhanced fibroblast activation and dermal fibrosis. Together, we demonstrate that Tregs play a critical role in regulating fibroblast activation in skin and do so by expressing a unique tissue-restricted transcriptional program that is mediated, at least in part, by GATA3.
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Nguyen, Vu H., Daisy Chang, and Robert S. Negrin. "Allogeneic Environment and Tissue Damage Provide Critical Stimuli for Regulatory T Cell Expansion and Survival In Vivo after Hematopoietic Cell Transplantation." Blood 108, no. 11 (November 16, 2006): 1731. http://dx.doi.org/10.1182/blood.v108.11.1731.1731.
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Abstract CD4+CD25+ regulatory T cells (Treg) mediate alloresponses in murine models of bone marrow transplantation (BMT), leading to protection from graft-versus-host disease (GvHD). However, in vivo migration and tissue localization of Treg during this inflammatory response remain unclear. We previously demonstrated co-localization of Treg with effector T cells (Tcon) with initial expansion in secondary lymphoid organs prior to migration into inflamed tissues in a major MHC-mismatched BMT model. To explore the stimuli for Treg proliferation, we evaluated the role of the allogeneic environment by transferring FVB donor luciferase-expressing (luc+) Treg into lethally-irradiated syngeneic recipients. Unlike the allogeneic irradiated setting where Treg expand in the presence or absence of Tcon, adoptively transferred luc+ Treg were not detected in secondary lymphoid organs of syngeneic lethally-irradiated BMT recipients by in vivo bioluminescence imaging (BLI). Syngeneic luc+ Tcon also had significantly different in vivo dynamics, with a 4 day delay and only moderate expansion in lymph nodes. Proliferation was not detected in the spleen, unlike their allogeneic Tcon counterparts, nor in the bone marrow compartments, as seen in lymphopenic models. To assess whether irradiation induced the observed in vivo dynamics of Treg in the allogeneic setting, we transferred FVB luc+ Treg or luc+ Tcon into unirradiated Balb/c Rag2−/−gamma chain (γC) −/− recipients, which lack T, B, and NK cells. After adoptive transfer into Rag2−/−γC−/− recipients, robust Tcon proliferation was observed in secondary lymphoid organs and the bone marrow compartments; however, Treg expansion was weak, and specific localization to lymphoid or nonlymphoid tissues was not observed. Treg were stimulated to localize to and expand in secondary lymphoid organs by the co-transfer of Tcon in unirradiated Rag2−/− (γC) −/− or by conditioning Rag2−/− (γC) −/− recipients with irradiation. Exogenous IL2 administration two weeks following luc+ Treg transfer into unirradiated Rag2−/− (γC) −/− recipients similarly led to localization and expansion of Treg in secondary lymphoid organs. These studies indicate the critical role of proinflammatory cytokines, such as IL2, generated either by irradiation-induced tissue damage or donor Tcon, in the expansion and localization of Treg. Differences between Tcon and Treg expansion in syngeneic or unconditioned allogeneic Rag2−/− γC−/− hosts suggest an important role of conditioning with irradiation alone or in concert with the allogeneic environment, in providing distinct signals for Tcon versus Treg activation, proliferation, and localization.
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Bag, Arup K., Andrew R. Schultz, Payal Goala, Florian A. Karreth, and Dennis O. Adeegbe. "Investigating the role of KLRG1 in regulatory T-cells and implications for anti-tumor immunity in Non-small Cell Lung Cancer." Journal of Immunology 206, no. 1_Supplement (May 1, 2021): 57.02. http://dx.doi.org/10.4049/jimmunol.206.supp.57.02.
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Abstract Although it is well established that CD4+CD25+Foxp3+ regulatory T cells (Tregs) dampen anti-tumor T cell responses in cancer, their molecular signature and clonal heterogeneity in NSCLC remains poorly understood. In this study, comparative phenotypic assessment of tumor and lymphoid tissue resident Tregs in KRAS/p53 mutant NSCLC mouse model revealed the presence of a distinct tumor infiltrating Treg population which express KLRG1. Compared to their counterparts, tumor associated KLRG1+ Treg showed higher expression of inhibitory receptors and activation markers, suggesting that KLRG1+ Tregs represent an activated subpopulation which may contribute to immunosuppression. Ex-vivo Treg suppression assay revealed that tumor associated KLGR1+ Tregs exhibited higher suppressive activity compared to KLRG1-Tregs. Although T cell development was normal in in-house generated KLRG1 KO mice including thymic and peripheral Treg numbers, KLRG1 KO Tregs showed less suppressive capacity compared to wild type, implying KLRG1 in Tregs functional program. Furthermore, α-KLRG1 antibody treatment in lung tumor bearing KP mice showed prolonged survival, accompanied by reduced proportion of KLRG1+ Tregs in the tumor. Finally, immunogenomic characterization of KLRG1 KO/wt and tumor infiltrating KLRG1+/− Tregs revealed distinct gene expression patterns and associated immune pathways. Collectively, our findings indicate that KLRG1 is not critical for Treg development and maintenance but may play a non-redundant role in Tregs differentiation and function in inflammatory settings. Therefore, targeting KLRG1 to curtail the inhibitory function of the highly suppressive KLRG1+ Treg subset could facilitate antitumor responses in NSCLC.